4-acylaminopyridine derivative

ABSTRACT

A novel 4-acylaminopyridine derivative represented by the following formula (I) is disclosed. ##STR1## The 4-acylaminopyridine derivative of the present invention is useful as a medicine for treating disturbances of memory such as senile dementia and Alzheimer&#39;s disease, since it has an action of directly activating malfunctioned cholinergic neuron.

This application is a Continuation of application Ser. No. 07/853,519,filed on Mar. 18, 1992 , now abandoned, which is a continuation of Ser.No. 07/610,059 filed Nov. 7, 1990 which is now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to a novel 4-acylaminopyridine derivativeand a pharmaceutically acceptable acid-added salt thereof useful foractivating a malfunctioned cholinergic neuron.

As a therapeutic treatment for various disturbances of memory such asAlzheimer's disease characterized by malfunction of a cholinergicneuron, has been made an attempt to increase the acetylcholine contentin the brain by using an antiacetylcholinesterase. For example,investigation on the use of physostigmine is reported in Neurology, 8,397(1978). Japanese Patent Application Laid-Open (KOKAI) Nos.61-148154(1986), 63-141980(1988), 63-225358(1988), 63-238063(1988),63-239271(1988), 63-284175(1988), 63-297367(1988), 64-73(1989) and1-132566(1989), EP-A-268871 and International Publication of PCT88/02256 report that a particular derivative of9-aminotetrahydroacridine has an antiacetylchorinesterase activity andis therefore useful for treatment of Alzheimer's disease.

Summers reports in The New England Journal of Medicine, 315, 1241(1986)that 9-amino-1,2,3,4-tetrahydroacridine (tacrine) is effective fortreatment of Alzheimer's disease when used together with lecithin.However, improvement is still insufficient and it produces undesirableside effects, and therefore, a new therapeutic treatment has beendemanded.

As examples of the known 9-acylaminotetrahydroacridines,9-acetylaminotetrahydroacridine is described in Journal of ChemicalSociety, 634(1947) and 9-chloroacetylaminotetrahydroacridine and9-diethylaminoacetylaminotetrahydroacridine are described in Chem.listy, 51, 1907(1957). 9-Diethylaminoacetylaminotetrahydroacridine isdescribed to have a local anesthetic action. In Journal of MedicinalChemistry, 18, 1056(1975), structure-activity correlation onantiacetylcholinesterase activity of 9-aminotetrahydroacridinederivatives and it is reported that the activity of9-acetylaminotetrahydroacridine and 9-benzoylaminotetrahydroacridine is1/1000 of the activity of 9-aminotetrahydroacridine. Some of JapanesePatent Application Laid-Open (KOKAI) Nos. 63-166881(1988),63-203664(1988), 63-238063(1988), 63-239271(1988), 63-284175(1988),64-73(1989) and 1-132566(1989) claims a 9-acylaminotetrahydroacridinederivative, however, none of them disclose expressly the synthesis ofnor a pharmaceutical activity of a compound having a 9-acylamino group.

The present inventors have made various and extensive studies so as toprovide a medicine effective for treatment of senile dementia includingAlzheimer's disease. As the result thereof, it has been found that aparticular 4-acylaminopyridine derivative and a pharmaceuticallyacceptable acid-added salt thereof can improve disturbances of memorysuch as Alzheimer's disease by a mechanism different from that of aconventionally known compound having an antiacetylcholinesteraseactivity. The present invention has been accomplished based on thisfinding.

SUMMARY OF THE INVENTION

The present invention provides a 4-acylaminopyridine derivativerepresented by the following formula (I): ##STR2## wherein R¹ representsa C₂ -C₆ alkyl group or a group represented by the following formula(II): ##STR3## wherein each of R² and R³ independently represents ahydrogen atom, C₁ -C₆ alkyl group, C₃ -C₆ cycloalkyl group or ##STR4##wherein each of R⁴ and R⁵ independently represents a hydrogen atom or C₁-C₆ alkyl group, or R² and R³ together with the nitrogen atom to whichboth R² and R³ are attached represent ##STR5## or ##STR6## wherein R⁶represents a hydrogen atom or C₁ -C₆ alkyl group, and n represents 0 oran integer from 1 to 3; ##STR7## represents ##STR8## wherein R⁷represents a hydrogen atom, C₁ -C₆ alkyl group or halogen atom, ##STR9##wherein each of R⁸ and R⁹ independently represents a hydrogen atom or C₁-C₄ alkyl group, ##STR10## wherein each of R¹⁰ and R¹¹ independentlyrepresents a hydrogen atom or a C₁ -C₄ alkyl group, ##STR11## represents##STR12## wherein each of R¹² and R¹³ independently represents ahydrogen atom or C₁ -C₄ alkyl group or R¹² and R¹³ may be combinedtogether to form a C₂ -C₆ alkylene group, ##STR13## with the provisothat when R¹ is a C₂ -C₆ alkyl group or a group represented by theformula (II) wherein one of R² and R³ is a hydrogen atom or C₁ -C₆ alkylgroup and the other of R² and R³ is a hydrogen atom or --CH₂ COOR⁵wherein R⁵ is the same as defined above, or R² and R³ together with thenitrogen atom to which both R² and R³ are attached represent ##STR14##and n is 1 or 2, is not ##STR15## wherein R⁷ is the same as definedabove, or is not ##STR16## wherein R⁹ is the same as defined above, and##STR17## is not ##STR18## wherein R¹² represents a hydrogen atom or C₁-C₄ alkyl group or is not ##STR19## and a pharmaceutically acceptableacid-added salt thereof.

The present invention further provides a pharmaceutical compositioncomprising a pharmaceutically effective amount of a 4-acylaminopyridinederivative represented by the formula (I) or a pharmaceuticallyacceptable acid-added salt thereof, and a pharmaceutically acceptableadjuvant.

The present invention still further provides a process for producing a4-acylaminopyridine derivative represented by the formula (I) and apharmaceutically acceptable acid-added salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The 4-acylaminopyridine derivative according to the present invention isrepresented by the formula (I) shown above.

In the formula (I), as examples of C₂ -C₆ alkyl group (alkyl grouphaving 2 to 6 carbon atoms) represented by R¹, ethyl group, n-propylgroup, isopropyl group, n-butyl group, sec-butyl group, tert-butylgroup, n-pentyl group and n-hexyl group may be mentioned. Among these, aC₂ -C₄ alkyl group is particularly preferable.

Examples of C₁ -C₆ alkyl group represented by each of R² to R⁷ aremethyl group, ethyl group, n-propyl group, isopropyl group, n-butylgroup, sec-butyl group, tert-butyl group, n-pentyl group and n-hexylgroup. Among these, a C₁ -C₄ alkyl group is preferable.

As C₃ -C₆ cycloalkyl group represented by each of R² and R³, cyclopropylgroup, cyclobutyl group, cyclopentyl group and cyclohexyl group may bementioned.

A halogen atom represented by R⁷ is exemplified by fluorine atom,chlorine atom, bromine atom and iodine atom.

As examples of C₁ -C₄ alkyl group represented by each of R⁸ to R¹³,methyl group, ethyl group, n-propyl group, isopropyl group, n-butylgroup, sec-butyl group and tert-butyl group may be mentioned.

In the present invention, among the compounds represented by the formula(I), is preferred a compound wherein R¹ represents a C₂ -C₆ alkyl groupor a group represented by the following formula (II): ##STR20## whereinR² represents a hydrogen atom or C₁ -C₆ alkyl group, R³ represents ahydrogen atom, C₁ -C₆ alkyl group, C₃ -C₆ cycloalkyl group ##STR21##wherein each of R⁴ and R⁵ independently represents a hydrogen atom or C₁-C₆ alkyl group, or R² and R³ together with the nitrogen atom to whichboth R² and R³ are attached represent ##STR22## wherein R⁶ represents ahydrogen atom or C₁ -C₆ alkyl group, and n represents 0 or an integerfrom 1 to 3; ##STR23## represents ##STR24## wherein R⁷ represents ahydrogen atom, C₁ -C₆ alkyl group or halogen atom, ##STR25## whereineach of R⁸ and R⁹ independently represents a hydrogen atom or C₁ -C₄alkyl group, or ##STR26## wherein each of R¹⁰ and R¹¹ independentlyrepresents a hydrogen atom or a C₁ -C₄ alkyl group; and ##STR27##represents ##STR28## wherein each of R¹² and R¹³ independentlyrepresents a hydrogen atom or C₁ -C₄ alkyl group or R¹² and R¹³ may becombined together to form a C₂ -C₆ alkylene group, or ##STR29##

More preferred is a compound wherein ##STR30## represents ##STR31##wherein R⁷ to R ¹¹ are the same as defined above.

The acid-added salt of the compound represented by the formula (I) ispreferred to be pharmaceutically and physiologically acceptable. Forexample, inorganic acid-added salts such as hydrochloride, hydrobromine,hydroiodide, sulfate and phosphate, and organic acid-added salts such asoxalate, maleate, fumarate, lactate, malate, citrate, tartrate,benzoate, methanesulfonate and camphorsulfonate may be mentioned. Thecompound represented by the formula (I) and the acid-added salt thereofcan be present in the form of hydrate or solvate. These hydrate andsolvate are also included in the compound of the present invention.

A process for producing the compound of the present invention will nowbe explained.

The compound represented by the formula (I) is produced by, for example,any of the following processes (1) to (5). ##STR32##

In the above reaction scheme, ##STR33## in the formulae (III) and (V)are the same as defined above, and R¹⁴ in the formulae (IV) and (V)represents a C₁ -C₆ alkyl group or C₃ -C₆ cycloalkyl group. Through theprocess (1), the compound of the present invention represented by theformula (V) can be produced by reacting a primary aromatic amine of theformula (III) with an isocyanate compound of the formula (IV).

As the reaction solvent, a halogen solvent such as dichloromethane,1,2-dichloroethane and 1,1,2,2-tetrachloroethane or an inert polarsolvent such as tetrahydrofuran, dioxane, acetonitrile,dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone may bepreferably used.

The reaction may be carried out at a temperature from 0° to 120° C.,preferably 20° to 80° C. ##STR34##

In the above reaction scheme, ##STR35## in the formulae (III), (VI) and(I₁) and R² and R³ in the formulae (VII) and (I₁) are the same asdefined above. Through the process (2), the compound of the presentinvention represented by the formula (I₁ ) can be produced by reacting acompound of the formula (HI) with excess trichloroacetyl chloride(reaction (a)) to obtain and isolate a trichloroacetamide compound ofthe formula (VI), and then reacting the compound of the formula (VI)with an amine of the formula (VII) or acetate thereof (reaction (b)).

The reaction (a) is carried out by using trichloroacetyl chloride alsoas the solvent at a temperature from 80° to 115° C., preferably from100° to 115° C.

The reaction (b) is carried out preferably in an inert solvent such astetrahydrofuron, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, etc. The reaction temperature is from 0°to 100° C., preferably from 0° to 50° C. when the amine is used, andfrom 50° to 160° C., preferably from 100° to 150° C. when the acetate ofthe amine is used. ##STR36##

In the above reaction scheme, ##STR37## in the formulae (III) and (I₁),and R² and R³ in the formulae (VII) and (I₁) are the same as definedabove. Through the process (3), the compound of the present inventionrepresented by the formula (I₁) can be produces. More in detail, thecompound of the formula (III) is dissolved in an inert solvent such asmethylene chloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane,benzene, toluene, xylene, tetrahydrofuran and dioxane, then, a phosgenecompound such as ditrichloromethyl carbonate, phosgene andtrichloromethyl chloroformate is added to the solution, followed by theaddition of a tertiary amine such as triethylamine. The thus obtainedsolution is added dropwise to a solvent containing the amine representedby the formula (VII) to give the compound represented by the formula(I₁). As the solvent for dissolving the amine represented by the formula(VII), tetrahydrofuran, dioxane, acetonitrile and alcohols arepreferable, and it is possible to use a raked solvent of water with atleast one of the above-described solvents, if necessary.

In the above reaction (c), the addition of the phosgene compound and theaddition of the tertiary amine are carried out at a temperature from-10° to 50° C., preferably from 0° to 30° C. The reaction with the aminerepresented by the formula (VII) is carried out at a temperature from-20° to 30° C., preferably from -10° to 20° C.

Process (4 )

(1) By reacting the compound represented by the formula (III): ##STR38##wherein ##STR39## have the same meanings as defined in the above formula(I), with a reactive derivative of the compound represented by theformula (VII): ##STR40## wherein R¹⁵ represents a C₂ -C₆ alkyl group,the compound represented by the formula (I₂) of the present inventioncan be obtained. ##STR41## wherein ##STR42## and R¹⁵ have the samemeanigs as defined above.

Examples of the reactive derivatives of the compound of the formula(VIII) are preferably symmetric acid anhydrides or acid halides,particularly acid chloride. The reaction is carried out in the presenceof of an inert solvent such as benzene, toluene, xylene,1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., or by usingexcessive amounts of symmetric acid anhydrides or acid halides as asolvent. When the symmetric acid anhydrides are used, a tertiary aminesuch as pyridine may be preferably used. The reaction is carried out ata temperature in the range of 30° to 150° C., preferably 50° to 120° C.

(2) After processing the compound represented by the above formula (III)with an equimolar amount or more of sodium hydride to prepare a sodiumsalt, reacting it with an ester compound represented by the formula(IX): ##STR43## wherein R¹⁶ represents ##STR44## (wherein ι representsan integer from 1 to 3), and R¹⁷ represents a methyl group or an ethylgroup, to obtain the compound represented by the formula (I₃): ##STR45##wherein ##STR46## and R¹⁶ have the same meanigs as defined above.

As the solvent, preferred are tetrahydrofuran, dioxane, acetonitrile,dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc. Thereaction is carried out at a temperature in the range of 10° to 80° C.,preferably 30° to 60° C. ##STR47## wherein X represents a chlorine atomor a bromine atom; ι represents 1, 2 or 3; ##STR48## have the samemeanings as defined in the formula (I); R¹⁸ in the formula (XII)represents a C₁ -C₆ alkyl group or ##STR49## (wherein R⁴ and R⁵ have thesame meanings as defined in the formula (I); R¹⁹ in the formula (XIII)represents ##STR50##

By the above two steps of the reaction formulae, the compound of theformula (I₄) or (I₅) can be synthesized. ##STR51##

In the above formulae (I₄) and (I5), ##STR52## R¹⁸, R¹⁹ and ι have thesame meanings as defined above.

That is, an acyl halide compound of the formula (X) is reacted with thecompound of the formula (TIT) to obtain the compound of the formula (XI)[step (a)]. Then, to the compound of the formula (XI), the compound ofthe formula (XII) is reacted, or else a compound which is a sodium saltobtained by treating the compound of the formula (XIII) with sodiumhydride [step (b)], the corresponding compound (I) can be obtained.

The step (a) is carried out by using an excessive amount of acyl halidealso as the solvent, or by using an inert solvent such as benzene,toluene, xylene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., ata temperature in the range of 50° to 150° C., preferably 70° to 120° C.

The step (b) is carried out by using an excessive amount of amine alsoas the solvent, or by using an alcoholic solvent such as methanol,ethanol, n-propanol, isopropanol, n-butanol, etc., or a solvent such astetrahydrofuran, dioxane, acetonitrile, dimethylformamide,dimethylsulfoxide, etc., at a temperature in the range of 0° to 150° C.,preferably 20° to 100° C. When the sodium salt of the compound of theformula (XIII) is reacted, the reaction is carried out by using asolvent such as tetrahydrofuran, dioxane, acetonitrile,dimethylformamide, dimethylsulfoxide, etc., at a temperature in therange of 0° to 120° C., preferably 20° to 80° C.

Process (5)

The compound where R¹ is a group represented by the formula (II) And R²and R³ together with the nitrogen atom to which both R² and R³ areattached represent ##STR53## wherein R⁶ is the same as defined above,i.e. the compound represented by the formula (I₆), can be producedaccording to the following reaction scheme. ##STR54## wherein ##STR55##and R⁶ are the same as defined above and R²⁰ represents a C₁ -C₄ alkylgroup.

In more detail, the compound of the formula (I₆) can be obtained byheating the compound of the formula (XIV) together with 1 to 10equivalents of urea in the presence or absence of a solvent.

The compound of the formula (XIV), the starting material, can beobtained by the process described in process (4).

As the solvent for producing the compound of the formula (I₆), an inertpolar solvent such as dimethyl sulfoxide, dimethylformamide,dimethylaceamide and N-methylpyrrolidone is preferred.

The reaction temperature is from 120° to 190° C., preferably from 140°to 170° C.

The starting compound represented by the formula (III) can be easilysynthesized by, for example, the methods described in (a) TetrahedronLetters, 1277(1963), (b) Collect. Czech. Chem. Commun., 42, 2802(1977),and (c) Acta Chemica Scandinavica, B, 33, 313(1979) and similar methodsthereto.

It is also possible to synthesize the starting compound (III) inaccordance with the methods described in Japanese Patent ApplicationLaid-Open (KOKAI) Nos. 61-148154(1986), 63-141980(1988),63-166881(1988), 63-203664(1988), 63-225358(1988), 63-238063(1988),63-239271(1988), 63-297367(1988), 64-73(1989), 1-132566(1989) andEP-A-268871.

The acid-added salt of the compound represented by the formula (I) canbe easily obtained by a known method to prepare an acid-added salt of aquinoline or pyridine based compound.

Some of the starting compound represented by the formula (III) forproducing the compound of the present invention, which were producedaccording to the methods described in the above references are shown inTable 1 below.

                  TABLE 1                                                         ______________________________________                                         ##STR56##                                                                     No.Compound                                                                           ##STR57##                                                                                  ##STR58##    (°C.)Melting Point                  ______________________________________                                         1                                                                                     ##STR59##                                                                                  ##STR60##   199˜200                                2                                                                                     ##STR61##                                                                                  ##STR62##   162˜163                                3                                                                                     ##STR63##                                                                                  ##STR64##   203˜204                                4                                                                                     ##STR65##                                                                                  ##STR66##   141˜143                                5                                                                                     ##STR67##                                                                                  ##STR68##   201˜204                                6                                                                                     ##STR69##                                                                                  ##STR70##   206˜207                                7                                                                                     ##STR71##                                                                                  ##STR72##   156˜158                                8                                                                                     ##STR73##                                                                                  ##STR74##   213˜214                                9                                                                                     ##STR75##                                                                                  ##STR76##   238˜242                               10                                                                                     ##STR77##                                                                                  ##STR78##   138˜139                               ______________________________________                                    

The compound of the present invention is used as a therapeutic medicineby administrating it singly or in the form of a mixture with apharmaceutically acceptable carrier. The composition is determined basedon the solubility and property of the compound to be used as the activeingredient, the administration route and dosage regimen. For example,the compound of the present invention may be orally administered in theform of granule, subtilized granule, powder, tablet, hard capsule, softcapsule, syrup, emulsion, suspension and solution. The compound of thepresent invention may be also administered intravenously,intramuscularly or subcutaneously by injection. The compound of thepresent invention may be prepared to an injectable powder and injectedafter dissolving or suspending in an appropriate solvent when used.

It is possible to use an organic or inorganic, solid or liquid carrieror diluent, which is suitable for oral, intestinal, parenteral or localadministration, together with the compound of the present invention. Asa vehicle for a solid preparation, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin and calcium carbonate are usable. A liquidpreparation for oral administration, i.e. emulsion, syrup, suspension,solution, etc., contains a usual diluent such as water, vegetable oil,etc. The liquid preparation can contain an auxiliary such as ahumectant, suspending agent, sweetening agent, aromatic, coloring agent,preservative etc: in addition to the inert diluent. The liquidpreparation may be encapsulated in an absorbable wall substance such asgelatin. As a solvent or a suspending agent used for preparing aparenteral preparation such as an injection preparation, water,propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate andlecithin may be mentioned. The preparation may be carried out by anordinary method.

The daily clinical dosage of the compound of the present invention inoral administration is usually 1 to 1000 mg, preferably 1 to 100 mg foran adult. It is preferable to appropriately increase or decrease thedose depending upon the age of patient, condition of disease, conditionof patient, and whether or not another medicine is administered. Thedaily dose of the compound of the present invention may be administeredat once, or in two or three .portions with appropriate interval.Intermittent administration thereof is also applicable.

The daily dosage of the compound of the present invention in injectionis 0.1 to 100 mg, preferably 0.1 to 50 mg for an adult.

Although the antiacetylcholinesterase activity of the compoundrepresented by the formula (I) is 1/100 of that of known9-aminotetrahydroacridine, the compound of the present invention canreactivate the presynaptic site of the cholinergic neuron to enhance theneurotransmission. More precisely, the compound of the present inventionimproves the reduced high-affinity choline-uptake in the hippocampaksynaptosome of a rat treated with AF64A (ethylcholine aziridinium ion;J.Pharmacol. Exp. Ther., 222, 140(1982) and Neuropharmacol., 26,361(1982)) intra-cerebroventricularly (Test Example 1 below). This kindof action is not observed in 9-aminotetrahydroacridine.

Further, the compound of the present invention is very low in toxicityand scarcely produces side effect in comparison with9-aminotetrahydroacridine, and therefore, the compound of the presentinvention can be a useful medicine for treating disturbances of memorysuch Alzheimer's disease.

The compound of the present invention represented by the formula (I) isa pharmaceutically active and valuable compound. Especially, thecompound of the present invention is useful as a medicine for treatingdisturbances of memory such as senile dementia and Alzheimer's disease,since it has an action on the activating malfunctioned cholinergicneuron.

In senile dementia, in particular, Alzheimer's disease, the function ofthe cholinergic neuron in the brain is decreased, and it is recognizedthat there is a good correlation between the deficit in the cholinergicneuron and the degree of disturbances in memory.

As reported by Fisher (J. Pharmacol. Exp. Ther., 222, 140(1982)) andLeventer (Neuropharmacol, 26, 361(1987)), AF64A causes long-termmalfunction selectively on cholinergic neuron, and disturbance of memoryand learning is observed in a rat to which AF64A is administered. Such arat is used as a good model of Alzheimer's disease. Therefore, from theabove pharmacological results, the compound of the present invention isconsidered to be useful for treating senile dementia includingAlzheimer's disease.

EXAMPLES

The present invention will be explained in more detail with reference tothe following examples, but it is to be understood that the presentinvention is not restricted to the following examples and anymodification is possible within the scope of the present invention.

Example 1 Synthesis ofN-(3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]-quinolin-4-yl)butanamide

To 4.37g of 4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline,were added 8 ml of pyridine and 12.7g of n-butyric anhydride and themixture was refluxed for 13 hours. The reaction mixture was evaporatedto dryness under a reduced pressure, and dissolved in 170 ml of methanoland 40 ml of ethanol. To the solution, was added 70 ml of concentratedammonia water and the reaction was carried out at 65° C. for 1.5 hours.

The solvent was evaporated under a reduced pressure and 100 ml ofchloroform, 100 ml of water and 5 ml of concentrated ammonia water wereadded, followed by stirring. The chloroform layer was dried overanhydrous sodium sulfate.

The chloroform solution was evaporated. The obtained product waspurified by silica gel column chromatography (chloroform-methanol) andwas recrystallized from chloroform-diethyl ether to obtain 5.11g of thetitled compound having the melting point of 200° to 202° C.

Examples 2 to 13

Each of the compounds listed in Table 2 was synthesized in the samemanner as in Example 1.

                  TABLE 2                                                         ______________________________________                                         ##STR79##                                                                     No.Example                                                                           ##STR80##                                                                                   ##STR81##    (°C.)Melting Point                  ______________________________________                                         2                                                                                    ##STR82##                                                                                   ##STR83##   201˜203                                3                                                                                    ##STR84##                                                                                   ##STR85##   192˜194                                4                                                                                    ##STR86##                                                                                   ##STR87##   183˜184                                5                                                                                    ##STR88##                                                                                   ##STR89##   175˜176                                6                                                                                    ##STR90##                                                                                   ##STR91##   168˜170                                7                                                                                    ##STR92##                                                                                   ##STR93##   164˜165                                8                                                                                    ##STR94##                                                                                   ##STR95##   205˜206                                9                                                                                    ##STR96##                                                                                   ##STR97##   188˜190                               10                                                                                    ##STR98##                                                                                   ##STR99##   204˜206                               11                                                                                    ##STR100##                                                                                  ##STR101##   88˜91                                12                                                                                    ##STR102##                                                                                  ##STR103##  193˜194                               13                                                                                    ##STR104##                                                                                  ##STR105##  159˜161                               ______________________________________                                    

Example 14 Synthesis ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]-quinolin-4-yl)isobutanamide

The titled compound having the melting point of 245° to 246° C. wasobtained in the same way as in Example 10 except for using isobutyricanhydride in place of n-butyric anhydride.

Example 15 Synthesis of2-(2-oxopyrrolidin-1-yl)-N-(3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-4-yl)aceamide

Into a suspension of 1.26 g of sodium hydride (60% content) in 15 ml ofN-methylpyrrolidone, was added 3.28 g of4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline at roomtemperature. The mixture was heated to 50° C. and stirred for 40minutes. Thereafter, 4.72 g of methyl 2-oxo-1-pyrrolidine acetate wasadded dropwise to the mixture at 50° C. over a period of 30 minutes.After the stirring at 50° C. for 20 minutes, the mixture was cooled to15° C. and poured into 130 ml aqueous solution containing 13.5 g ofammonium chloride.

After extraction of the solution with 100 ml of chloroform, the extractwas dried over anhydrous sodium sulfate, followed by evaporation todryness. The resultant product was added with ethyl acetate, pulverizedand filtered. The crude crystals were recrystallized fromchloroform-ethyl acetate to obtain 4.31 g of the titled compound havingthe melting point of 244° to 246° C.

Examples 16 to 29

Each of the compounds listed in Table 3 was synthesized in the same wayas in Example 15.

                  TABLE 3                                                         ______________________________________                                         ##STR106##                                                                    No.Example                                                                           ##STR107##                                                                                  ##STR108##   (°C.)Melting Point                  ______________________________________                                        16                                                                                    ##STR109##                                                                                  ##STR110##  217˜220                               17                                                                                    ##STR111##                                                                                  ##STR112##  222˜225                               18                                                                                    ##STR113##                                                                                  ##STR114##  244˜246                               19                                                                                    ##STR115##                                                                                  ##STR116##  203˜204                               20                                                                                    ##STR117##                                                                                  ##STR118##  192˜194                               21                                                                                    ##STR119##                                                                                  ##STR120##  168˜170                               22                                                                                    ##STR121##                                                                                  ##STR122##  161˜163 hydrochloride                 23                                                                                    ##STR123##                                                                                  ##STR124##  216˜218                               24                                                                                    ##STR125##                                                                                  ##STR126##  210˜212                               25                                                                                    ##STR127##                                                                                  ##STR128##  213˜215                               26                                                                                    ##STR129##                                                                                  ##STR130##  189˜191                               27                                                                                    ##STR131##                                                                                  ##STR132##  193˜195                               28                                                                                    ##STR133##                                                                                  ##STR134##  216˜217                               29                                                                                    ##STR135##                                                                                  ##STR136##  159˜161                               ______________________________________                                    

Example 30 Synthesis ofN-(5,6,7,8-tetrahydrothieno[2,3-b]quinolin-4-yl)urea

A mixture of 8.17 g of 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolineand 90 ml of trichloroacetyl chloride was refluxed for 4 hours. Themixture was cooled to 25° C. and 30 ml of 1,2-dichloroethane was addedthereto. The crystals were filtered out and washed with1,2-dichloroethane.

The suspension of the crystals in 200 ml of chloroform and 120 ml ofwater was added with 5 ml of concentrated ammonia water. After thechloroform layer was dried over anhydrous sodium sulfate, it waspurified by silica gel column chromatography (chloroform). Byrecrystallization from chloroform-n-heptane, 11.84 g ofN-(5,6,7,8-tetrahydrothieno[2,3-b]quinolin-4-yl)trichloroacetamidehaving the melting point of 176° to 178° C. was obtained.

In 20 ml of N-methylpyrrolidone, was dissolved 3.5 g of the obtainedcompound. After adding 6.2 g of ammonium acetate to the solution, thereaction was carried out at 150° C. for 30 minutes. After cooled to 30°C., the reaction mixture was added with 100 ml of water and 50 ml ofchloroform, followed by stirring. The pH of the aqueous layer of themixture was adjusted to 10 with concentrated ammonia water.

The insoluble matters were collected by filtration and washed withchloroform and water, followed by recrystallization fromethanol-1,1,2,2-tetrachloroethane-ethyl acetate to obtain 0.73 g of thetitled compound having the melting point of 260° to 262° C.

Example 31 Synthesis ofN-methyl-N'-(5,6,7,8-tetrahydrothieno[2,3-b]quinolin-4-yl)urea

In 120 ml of 1,1,2,2-tetrachloroethane, was dissolved 2.45 g of4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline, and 1.78 g ofditrichloromethyl carbonate was added to the solution at a temperaturefrom 20° to 30° C.

After adding 6.7 g of triethylamine at a temperature from 20° to 30° C.,the mixture was stirred for one hour at room temperature.

Separately, 70 ml of 40% methanol solution of methylamine was cooled at-10° C. The reaction mixture was added dropwise to the methanol solutionat 0° C. and heated to 30° C. in one hour.

Then, 150 ml of water and 120 ml of chloroform were added to the mixtureand the insoluble matters were filtered out, followed byrecrystallization from methanol-chloroform to obtain 2.49 g of thetitled compound having the melting point of 253° to 255° C.

Examples 32 to 37

Compounds shown in Table 4 were synthesized in the same way as inExample 31.

                  TABLE 4                                                         ______________________________________                                         ##STR137##                                                                   Ex- am- ple No.                                                                     ##STR138##                                                                                 ##STR139##                                                                              R.sup.2                                                                            R.sup.3                                                                              (°C.)PointMelting             ______________________________________                                        32                                                                                  ##STR140##                                                                                 ##STR141##                                                                             H    H      216˜218                         33                                                                                  ##STR142##                                                                                 ##STR143##                                                                             H    H      220˜235 Decom- posed            34                                                                                  ##STR144##                                                                                 ##STR145##                                                                             CH.sub.3                                                                           CH.sub.3                                                                             211˜216                         35                                                                                  ##STR146##                                                                                 ##STR147##                                                                             CH.sub.3                                                                           CH.sub.3                                                                             215˜218                         36                                                                                  ##STR148##                                                                                 ##STR149##                                                                             H                                                                                   ##STR150##                                                                          248˜250                         37                                                                                  ##STR151##                                                                                 ##STR152##                                                                             H    H      292˜294                         ______________________________________                                    

Example 38 Synthesis ofN-[(1,2,3,4-tetrahydroacridin-9-yl)aminocarbonylmethyl]-L-alanine ethylester

To 5 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine, was added 22 gof L-alanine ethyl ester and the reaction was continued for 30 minutesat 100° C. After cooled to room temperature, the reaction mixture wasadded with 100 ml of chloroform and 100 ml of water and stirred. Thechloroform layer was dried over anhydrous sodium sulfate and purified bysilica gel column chromatography (chloroformmethanol), followed byrecrystallization from chloroform-n-hexane to obtain 5.9 g of the titledcompound having the melting point of 101° to 102° C.

Example 39

Synthesis ofN-[(1,2,3,4-tetrahydroacridin-9-yl)aminocarbonylmethyl]-L-alanine

Into 12 ml of 1N aqueous solution of sodium hydroxide, was added 2 g ofthe compound obtained in Example 38 at room temperature, and thereaction was continued for 2 hours. To the reaction mixture, was added15 ml of 1N hydrochloric acid at a temperature not higher than 15° C. toprecipitate white crystals. The crystals were collected by filtration,washed with water and dried to obtain 1.42 g of the titled compoundhaving the melting point of 238° to 242° C. (decomposed).

Examples 40 to 42

Compounds shown in Table 5 were synthesized in the same way as inExample 38 or 39.

                  TABLE 5                                                         ______________________________________                                         ##STR153##                                                                   Ex- am- ple No.                                                                     ##STR154##                                                                              ##STR155##                                                                              R.sup.2                                                                           R.sup.3    (°C.)PointMelting             ______________________________________                                        40                                                                                  ##STR156##                                                                              ##STR157##                                                                             H                                                                                  ##STR158##                                                                              139˜140                         41                                                                                  ##STR159##                                                                              ##STR160##                                                                             H                                                                                  ##STR161##                                                                              127˜130                         42                                                                                  ##STR162##                                                                              ##STR163##                                                                             H                                                                                  ##STR164##                                                                              223˜226 Decom- posed            ______________________________________                                    

Reference Example 1 Synthesis of2-chloro-N-(3-methyl-5,6,7,8-tetrahydrothieno[2,3-b ]quinolin-4-yl)acetamide

To 12.7 g of 4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3b]quinoline,was added 40 ml of chloroacetyl chloride, and the mixture was refluxedfor 40 minutes. The oil bath was removed and the reaction mixture wasadded with 50 ml of 1,2-dichloroethane and cooled to 25° C. Theprecipitated crystals were collected by filtration and washed with1,2-dichloroethane. The crystals were suspended in a mixed solvent of250 ml of chloroform, 55 ml of water and 60 ml of ethanol, and 4.3 ml ofconcentrated ammonia water was added thereto. The suspension was heatedto 40° C. to dissolve substantially all the crystals.

The chloroform layer was dried over anhydrous sodium sulfate andconcentrated to a volume of about 100 ml. The chloroform solution wasadded with 40 ml of n-heptane and cooled, followed by filtration toobtain 8.2 g of the titled compound having the melting point of 233° to236° C.

Example 43 Synthesis of2-cyclopropylamino-N-(3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-4-yl)aceamide

To 12 ml of t-butanol and 25 ml of dimethylformamide, was added 2.1 g ofthe compound obtained in Reference Example 1. Then, 9 ml ofcyclopropylamine was added and the reaction was carried out at 100° C.for 30 minutes.

The reaction mixture was evaporated to dryness under a reduced pressure,then, 100 ml of chloroform, 30 ml of water and 5 ml of concentratedammonia water were added, followed by stirring. The chloroform layer wasdried over anhydrous sodium sulfate and purified by silica gel columnchromatography (chloroform-methanol), followed by recrystallization fromethyl acetate to obtain 1.52 g of titled compound having the meltingpoint of 141° to 144° C.

Examples 44 to 52

Compounds shown in Table 6 were synthesized in the way as in Example 43.

                                      TABLE 6                                     __________________________________________________________________________     ##STR165##                                                                    Example No.                                                                          ##STR166##                                                                             ##STR167##                                                                          ##STR168##                                                                             Melting Point (°C.)                    __________________________________________________________________________    44                                                                                    ##STR169##                                                                             ##STR170##                                                                          ##STR171##                                                                            Amorphous solid                                45                                                                                    ##STR172##                                                                             ##STR173##                                                                         CH.sub.3 142˜145                                  46                                                                                    ##STR174##                                                                             ##STR175##                                                                          ##STR176##                                                                            110˜111                                  47                                                                                    ##STR177##                                                                             ##STR178##                                                                         CH.sub.3 146˜149                                  48                                                                                    ##STR179##                                                                             ##STR180##                                                                         CH.sub.3 141˜143                                  49                                                                                    ##STR181##                                                                             ##STR182##                                                                         CH.sub.2CO.sub.2 CH.sub.3                                                              147˜149                                  50                                                                                    ##STR183##                                                                             ##STR184##                                                                         CH.sub.2CO.sub.2 H                                                                     221˜230 (Decomposed)                     51                                                                                    ##STR185##                                                                             ##STR186##                                                                          ##STR187##                                                                            245˜250                                  52                                                                                    ##STR188##                                                                             ##STR189##                                                                          ##STR190##                                                                            218˜222                                  __________________________________________________________________________

Example 53 Synthesis of2-((S)-5-methyl-2,4-dioxoimidazolidin-1-yl)-N-(1,2,3,4-tetrahydroacridin-9-yl )acetamide

In 9 ml of N-methylpyrrolidone, was dissolved 3.9 g of the compoundobtained in Example 38, and 2.64 g of urea was further added thereto.The reaction was carried out at 160° C. for one hour. The reactionmixture was cooled to 80° C. and 100 ml of water was added. Theprecipitated crystals were collected by filtration and dissolved in amixture of 5 ml of methanol and 150 ml of chloroform. The solution wasdried over anhydrous sodium sulfate and evaporated to dryness. Theobtained product was recrystallized from ethanol-ethyl acetate to obtain2.44 g of the titled compound having the melting point of 260° to 263°C.

Examples 54 to 60

Compounds shown in Table 7 were synthesized in the same way as inExample 53.

                  TABLE 7                                                         ______________________________________                                         ##STR191##                                                                   Ex- am- ple No.                                                                     ##STR192##                                                                                ##STR193##   R.sup.6                                                                               (°C.)PointMelting               ______________________________________                                        54                                                                                  ##STR194##                                                                                ##STR195##  H       280˜287 Decom- posed              55                                                                                  ##STR196##                                                                                ##STR197##                                                                                 ##STR198##                                                                           219˜223                           56                                                                                  ##STR199##                                                                                ##STR200##  H       279˜283 Decom- posed              57                                                                                  ##STR201##                                                                                ##STR202##  H       285˜295 Decom- posed Hydro-                                             chloride                                58                                                                                  ##STR203##                                                                                ##STR204##  H       261˜263                           59                                                                                  ##STR205##                                                                                ##STR206##  H       298˜301                           60                                                                                  ##STR207##                                                                                ##STR208##  H       270˜274                           ______________________________________                                    

Example 61 Synthesisof2-((S)-5-methyl-2,4-dioxoimidazolidin-1-yl)-N-(3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-4-yl)acetamide

In 8 ml of N-methylpyrrolidone, was dissolved 2.5 g of the compoundobtained in Example 44, and 8 g of urea was further added. The reactionwas continued at 160° C. for 40 minutes. The reaction mixture was cooledto 80° C. and further cooled to 25° C. after addition of 90 ml of water.The precipitated crystals were collected by filtration andrecrystallized from methanol-water to obtain 0.84 g. of the titledcompound having the melting point of 273° to 277° C.

Examples 62 to 65

Compound shown in Table 8 were synthesized in the same way as in Example61.

Compounds shown in Table 9 and Table 10 can be synthesized in the sameway as described in Examples above.

                                      TABLE 8                                     __________________________________________________________________________     ##STR209##                                                                    Example No.                                                                          ##STR210##                                                                             ##STR211##                                                                          ##STR212##                                                                               Melting Point (°C.)                  __________________________________________________________________________    62                                                                                    ##STR213##                                                                             ##STR214##                                                                          ##STR215##                                                                              197˜198                                63                                                                                    ##STR216##                                                                             ##STR217##                                                                          ##STR218##                                                                              242˜245                                64                                                                                    ##STR219##                                                                             ##STR220##                                                                          ##STR221##                                                                              274˜281                                65                                                                                    ##STR222##                                                                             ##STR223##                                                                          ##STR224##                                                                              158˜160                                __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________     ##STR225##                                                                    Compound No.                                                                          ##STR226##                                                                              ##STR227##                                                                              R.sup.1                                          __________________________________________________________________________    66                                                                                     ##STR228##                                                                              ##STR229##                                                                              ##STR230##                                       67                                                                                     ##STR231##                                                                              ##STR232##                                                                             C.sub.3 H.sub.7                                   68                                                                                     ##STR233##                                                                              ##STR234##                                                                             C.sub.3 H.sub.7                                   69                                                                                     ##STR235##                                                                              ##STR236##                                                                             C.sub.3 H.sub.7                                   70                                                                                     ##STR237##                                                                              ##STR238##                                                                             C.sub.3 H.sub.7                                   71                                                                                     ##STR239##                                                                              ##STR240##                                                                             C.sub.3 H.sub.7                                   72                                                                                     ##STR241##                                                                              ##STR242##                                                                             C.sub.3 H.sub.7                                   73                                                                                     ##STR243##                                                                              ##STR244##                                                                             C.sub.2 H.sub.5                                   74                                                                                     ##STR245##                                                                              ##STR246##                                                                              ##STR247##                                       75                                                                                     ##STR248##                                                                              ##STR249##                                                                             C.sub.4 H.sub.9                                   76                                                                                     ##STR250##                                                                              ##STR251##                                                                              ##STR252##                                       77                                                                                     ##STR253##                                                                              ##STR254##                                                                              ##STR255##                                       78                                                                                     ##STR256##                                                                              ##STR257##                                                                             C(CH.sub.3).sub.3                                 79                                                                                     ##STR258##                                                                              ##STR259##                                                                             C.sub.3 H.sub.7                                   80                                                                                     ##STR260##                                                                              ##STR261##                                                                             C.sub.3 H.sub.7                                   81                                                                                     ##STR262##                                                                              ##STR263##                                                                             C.sub.3 H.sub.7                                   82                                                                                     ##STR264##                                                                              ##STR265##                                                                             C.sub.3 H.sub.7                                   83                                                                                     ##STR266##                                                                              ##STR267##                                                                             C.sub.3 H.sub.7                                   84                                                                                     ##STR268##                                                                              ##STR269##                                                                             C.sub.3 H.sub.7                                   85                                                                                     ##STR270##                                                                              ##STR271##                                                                             C.sub.3 H.sub.7                                   86                                                                                     ##STR272##                                                                              ##STR273##                                                                             C.sub.3 H.sub.7                                   87                                                                                     ##STR274##                                                                              ##STR275##                                                                             C.sub.3 H.sub.7                                   88                                                                                     ##STR276##                                                                              ##STR277##                                                                             C.sub.3 H.sub.7                                   89                                                                                     ##STR278##                                                                              ##STR279##                                                                             C.sub.3 H.sub.7                                   90                                                                                     ##STR280##                                                                              ##STR281##                                                                             C.sub.3 H.sub.7                                   91                                                                                     ##STR282##                                                                              ##STR283##                                                                             C.sub.3 H.sub.7                                   92                                                                                     ##STR284##                                                                              ##STR285##                                                                             C.sub.3 H.sub.7                                   93                                                                                     ##STR286##                                                                              ##STR287##                                                                             C.sub.3 H.sub.7                                   94                                                                                     ##STR288##                                                                              ##STR289##                                                                             C.sub.3 H.sub.7                                   95                                                                                     ##STR290##                                                                              ##STR291##                                                                             C.sub.3 H.sub.7                                   __________________________________________________________________________

                                      TABLE 10                                    __________________________________________________________________________     ##STR292##                                                                    No.Compound                                                                         ##STR293##                                                                            ##STR294##                                                                             R.sup.2                                                                           R.sup.3   n                                       __________________________________________________________________________     96                                                                                  ##STR295##                                                                            ##STR296##                                                                            H   C.sub.2 H.sub.5                                                                         0                                         97                                                                                  ##STR297##                                                                            ##STR298##                                                                            H   C.sub.3 H.sub.7                                                                         0                                         98                                                                                  ##STR299##                                                                            ##STR300##                                                                            H                                                                                  ##STR301##                                                                             0                                         99                                                                                  ##STR302##                                                                            ##STR303##                                                                            H   C.sub.4 H.sub.9                                                                         0                                        100                                                                                  ##STR304##                                                                            ##STR305##                                                                            H                                                                                  ##STR306##                                                                             0                                        101                                                                                  ##STR307##                                                                            ##STR308##                                                                            H                                                                                  ##STR309##                                                                             0                                        102                                                                                  ##STR310##                                                                            ##STR311##                                                                            H                                                                                  ##STR312##                                                                             0                                        103                                                                                  ##STR313##                                                                            ##STR314##                                                                            H   H         0                                        104                                                                                  ##STR315##                                                                            ##STR316##                                                                            CH.sub.3                                                                          CH.sub.3  0                                        105                                                                                  ##STR317##                                                                            ##STR318##                                                                            H   H         0                                        106                                                                                  ##STR319##                                                                            ##STR320##                                                                            CH.sub.3                                                                          CH.sub.3  0                                        107                                                                                  ##STR321##                                                                            ##STR322##                                                                            CH.sub.3                                                                          CH.sub.3  0                                        108                                                                                  ##STR323##                                                                            ##STR324##                                                                            H   H         0                                        109                                                                                  ##STR325##                                                                            ##STR326##                                                                            CH.sub.3                                                                          CH.sub.3  0                                        110                                                                                  ##STR327##                                                                            ##STR328##                                                                            H   H         0                                        111                                                                                  ##STR329##                                                                            ##STR330##                                                                            H   CH.sub.3  0                                        112                                                                                  ##STR331##                                                                            ##STR332##                                                                            H   C.sub.2 H.sub.5                                                                         0                                        113                                                                                  ##STR333##                                                                            ##STR334##                                                                            H   C.sub.3 H.sub.7                                                                         0                                        114                                                                                  ##STR335##                                                                            ##STR336##                                                                            H                                                                                  ##STR337##                                                                             0                                        115                                                                                  ##STR338##                                                                            ##STR339##                                                                            CH.sub.3                                                                          CH.sub.3  0                                        116                                                                                  ##STR340##                                                                            ##STR341##                                                                            H   H         0                                        117                                                                                  ##STR342##                                                                            ##STR343##                                                                            H   H         0                                        118                                                                                  ##STR344##                                                                            ##STR345##                                                                            CH.sub.3                                                                          H         0                                        119                                                                                  ##STR346##                                                                            ##STR347##                                                                            CH.sub.3                                                                          CH.sub.3  0                                        120                                                                                  ##STR348##                                                                            ##STR349##                                                                            H   H         0                                        121                                                                                  ##STR350##                                                                            ##STR351##                                                                            H   H         0                                        122                                                                                  ##STR352##                                                                            ##STR353##                                                                            H   H         0                                        123                                                                                  ##STR354##                                                                            ##STR355##                                                                            H   CH.sub.3  1                                        124                                                                                  ##STR356##                                                                            ##STR357##                                                                            H   CH.sub.3  1                                        125                                                                                  ##STR358##                                                                            ##STR359##                                                                            H   CH.sub.3  1                                        126                                                                                  ##STR360##                                                                            ##STR361##                                                                            H   CH.sub.3  1                                        127                                                                                  ##STR362##                                                                            ##STR363##                                                                            H   CH.sub.3  1                                        128                                                                                  ##STR364##                                                                            ##STR365##                                                                            H   CH.sub.3  1                                        129                                                                                  ##STR366##                                                                            ##STR367##                                                                            H   CH.sub.3  1                                        130                                                                                  ##STR368##                                                                            ##STR369##                                                                            H   CH.sub.3  1                                        131                                                                                  ##STR370##                                                                            ##STR371##                                                                            H   CH.sub.3  1                                        132                                                                                  ##STR372##                                                                            ##STR373##                                                                            H   CH.sub.3  1                                        133                                                                                  ##STR374##                                                                            ##STR375##                                                                            H   C.sub.2 H.sub.5                                                                         1                                        134                                                                                  ##STR376##                                                                            ##STR377##                                                                            H   C.sub.3 H.sub.7                                                                         1                                        135                                                                                  ##STR378##                                                                            ##STR379##                                                                            H                                                                                  ##STR380##                                                                             1                                        136                                                                                  ##STR381##                                                                            ##STR382##                                                                            H   C.sub.4 H.sub.9                                                                         1                                        137                                                                                  ##STR383##                                                                            ##STR384##                                                                            H                                                                                  ##STR385##                                                                             1                                        138                                                                                  ##STR386##                                                                            ##STR387##                                                                            H                                                                                  ##STR388##                                                                             1                                        139                                                                                  ##STR389##                                                                            ##STR390##                                                                            H   C(CH.sub.3).sub.3                                                                       1                                        140                                                                                  ##STR391##                                                                            ##STR392##                                                                            H                                                                                  ##STR393##                                                                             1                                        141                                                                                  ##STR394##                                                                            ##STR395##                                                                            H   CH.sub.3  1                                        142                                                                                  ##STR396##                                                                            ##STR397##                                                                            H   CH.sub.3  1                                        143                                                                                  ##STR398##                                                                            ##STR399##                                                                            H   CH.sub.3  1                                        144                                                                                  ##STR400##                                                                            ##STR401##                                                                            H   CH.sub.3  1                                        145                                                                                  ##STR402##                                                                            ##STR403##                                                                            H   CH.sub.3  1                                        146                                                                                  ##STR404##                                                                            ##STR405##                                                                            H   CH.sub.3  1                                        147                                                                                  ##STR406##                                                                            ##STR407##                                                                            H   CH.sub.3  1                                        148                                                                                  ##STR408##                                                                            ##STR409##                                                                            H   CH.sub.3  1                                        149                                                                                  ##STR410##                                                                            ##STR411##                                                                            H   CH.sub.3  1                                        150                                                                                  ##STR412##                                                                            ##STR413##                                                                            H   CH.sub.3  1                                        151                                                                                  ##STR414##                                                                            ##STR415##                                                                            H   CH.sub.3  1                                        152                                                                                  ##STR416##                                                                            ##STR417##                                                                            H   CH.sub.3  1                                        153                                                                                  ##STR418##                                                                            ##STR419##                                                                            H   CH.sub.3  1                                        154                                                                                  ##STR420##                                                                            ##STR421##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        155                                                                                  ##STR422##                                                                            ##STR423##                                                                            H   CH.sub.2COOCH.sub.3                                                                     1                                        156                                                                                  ##STR424##                                                                            ##STR425##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        157                                                                                  ##STR426##                                                                            ##STR427##                                                                            H                                                                                  ##STR428##                                                                             1                                        158                                                                                  ##STR429##                                                                            ##STR430##                                                                            H                                                                                  ##STR431##                                                                             1                                        159                                                                                  ##STR432##                                                                            ##STR433##                                                                            H                                                                                  ##STR434##                                                                             1                                        160                                                                                  ##STR435##                                                                            ##STR436##                                                                            H                                                                                  ##STR437##                                                                             1                                        161                                                                                  ##STR438##                                                                            ##STR439##                                                                            H                                                                                  ##STR440##                                                                             1                                        162                                                                                  ##STR441##                                                                            ##STR442##                                                                            H                                                                                  ##STR443##                                                                             1                                        163                                                                                  ##STR444##                                                                            ##STR445##                                                                            H                                                                                  ##STR446##                                                                             1                                        164                                                                                  ##STR447##                                                                            ##STR448##                                                                            H                                                                                  ##STR449##                                                                             1                                        165                                                                                  ##STR450##                                                                            ##STR451##                                                                            H                                                                                  ##STR452##                                                                             1                                        166                                                                                  ##STR453##                                                                            ##STR454##                                                                            H                                                                                  ##STR455##                                                                             1                                        167                                                                                  ##STR456##                                                                            ##STR457##                                                                            H                                                                                  ##STR458##                                                                             1                                        168                                                                                  ##STR459##                                                                            ##STR460##                                                                            H                                                                                  ##STR461##                                                                             1                                        169                                                                                  ##STR462##                                                                            ##STR463##                                                                            H                                                                                  ##STR464##                                                                             1                                        170                                                                                  ##STR465##                                                                            ##STR466##                                                                            H                                                                                  ##STR467##                                                                             1                                        171                                                                                  ##STR468##                                                                            ##STR469##                                                                            H                                                                                  ##STR470##                                                                             1                                        172                                                                                  ##STR471##                                                                            ##STR472##                                                                            H                                                                                  ##STR473##                                                                             1                                        173                                                                                  ##STR474##                                                                            ##STR475##                                                                            H                                                                                  ##STR476##                                                                             1                                        174                                                                                  ##STR477##                                                                            ##STR478##                                                                            H                                                                                  ##STR479##                                                                             1                                        175                                                                                  ##STR480##                                                                            ##STR481##                                                                            H                                                                                  ##STR482##                                                                             1                                        176                                                                                  ##STR483##                                                                            ##STR484##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        177                                                                                  ##STR485##                                                                            ##STR486##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        178                                                                                  ##STR487##                                                                            ##STR488##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        179                                                                                  ##STR489##                                                                            ##STR490##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        180                                                                                  ##STR491##                                                                            ##STR492##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        181                                                                                  ##STR493##                                                                            ##STR494##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        182                                                                                  ##STR495##                                                                            ##STR496##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        183                                                                                  ##STR497##                                                                            ##STR498##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        184                                                                                  ##STR499##                                                                            ##STR500##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        185                                                                                  ##STR501##                                                                            ##STR502##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        186                                                                                  ##STR503##                                                                            ##STR504##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        187                                                                                  ##STR505##                                                                            ##STR506##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        188                                                                                  ##STR507##                                                                            ##STR508##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        189                                                                                  ##STR509##                                                                            ##STR510##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        190                                                                                  ##STR511##                                                                            ##STR512##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        191                                                                                  ##STR513##                                                                            ##STR514##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        192                                                                                  ##STR515##                                                                            ##STR516##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        193                                                                                  ##STR517##                                                                            ##STR518##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        194                                                                                  ##STR519##                                                                            ##STR520##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        195                                                                                  ##STR521##                                                                            ##STR522##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        196                                                                                  ##STR523##                                                                            ##STR524##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        197                                                                                  ##STR525##                                                                            ##STR526##                                                                            H   CH.sub.2COOC.sub.2 H.sub.5                                                              1                                        198                                                                                  ##STR527##                                                                            ##STR528##                                                                             ##STR529##   1                                        199                                                                                  ##STR530##                                                                            ##STR531##                                                                             ##STR532##   1                                        200                                                                                  ##STR533##                                                                            ##STR534##                                                                             ##STR535##   1                                        201                                                                                  ##STR536##                                                                            ##STR537##                                                                             ##STR538##   1                                        202                                                                                  ##STR539##                                                                            ##STR540##                                                                             ##STR541##   1                                        203                                                                                  ##STR542##                                                                            ##STR543##                                                                             ##STR544##   1                                        204                                                                                  ##STR545##                                                                            ##STR546##                                                                             ##STR547##   1                                        205                                                                                  ##STR548##                                                                            ##STR549##                                                                             ##STR550##   1                                        206                                                                                  ##STR551##                                                                            ##STR552##                                                                             ##STR553##   1                                        207                                                                                  ##STR554##                                                                            ##STR555##                                                                             ##STR556##   1                                        208                                                                                  ##STR557##                                                                            ##STR558##                                                                             ##STR559##   1                                        209                                                                                  ##STR560##                                                                            ##STR561##                                                                             ##STR562##   1                                        210                                                                                  ##STR563##                                                                            ##STR564##                                                                             ##STR565##   1                                        211                                                                                  ##STR566##                                                                            ##STR567##                                                                             ##STR568##   1                                        212                                                                                  ##STR569##                                                                            ##STR570##                                                                             ##STR571##   1                                        213                                                                                  ##STR572##                                                                            ##STR573##                                                                             ##STR574##   1                                        214                                                                                  ##STR575##                                                                            ##STR576##                                                                             ##STR577##   1                                        215                                                                                  ##STR578##                                                                            ##STR579##                                                                             ##STR580##   1                                        216                                                                                  ##STR581##                                                                            ##STR582##                                                                             ##STR583##   1                                        217                                                                                  ##STR584##                                                                            ##STR585##                                                                             ##STR586##   1                                        218                                                                                  ##STR587##                                                                            ##STR588##                                                                             ##STR589##   1                                        219                                                                                  ##STR590##                                                                            ##STR591##                                                                             ##STR592##   1                                        220                                                                                  ##STR593##                                                                            ##STR594##                                                                             ##STR595##   1                                        221                                                                                  ##STR596##                                                                            ##STR597##                                                                             ##STR598##   1                                        222                                                                                  ##STR599##                                                                            ##STR600##                                                                             ##STR601##   1                                        223                                                                                  ##STR602##                                                                            ##STR603##                                                                             ##STR604##   1                                        224                                                                                  ##STR605##                                                                            ##STR606##                                                                             ##STR607##   1                                        225                                                                                  ##STR608##                                                                            ##STR609##                                                                             ##STR610##   1                                        226                                                                                  ##STR611##                                                                            ##STR612##                                                                             ##STR613##   1                                        227                                                                                  ##STR614##                                                                            ##STR615##                                                                             ##STR616##   1                                        228                                                                                  ##STR617##                                                                            ##STR618##                                                                             ##STR619##   1                                        229                                                                                  ##STR620##                                                                            ##STR621##                                                                             ##STR622##   1                                        230                                                                                  ##STR623##                                                                            ##STR624##                                                                             ##STR625##   1                                        231                                                                                  ##STR626##                                                                            ##STR627##                                                                             ##STR628##   1                                        232                                                                                  ##STR629##                                                                            ##STR630##                                                                             ##STR631##   1                                        233                                                                                  ##STR632##                                                                            ##STR633##                                                                             ##STR634##   1                                        234                                                                                  ##STR635##                                                                            ##STR636##                                                                             ##STR637##   1                                        235                                                                                  ##STR638##                                                                            ##STR639##                                                                             ##STR640##   1                                        __________________________________________________________________________                   PG,85

Test Example 1

Na⁺ Dependent High-affinity Choline Uptake Ability (HACU) of the Brainof a Rat Treated with AF64A

AF64A was prepared from AF64 in accordance with the method of Fischer etal. (J. Pharmacol. Exp. Ther., 222, 140(1982)). AF64A (1.5 nmol/1.5μl/side) was injected into both the lateral ventricles of a rat. Oneweek after, the rat was decapitated and only the hippocampus was takenout. The hippocampus was homogenized with 0.32M of sucrose andcentrifuged at 1000 g for 10 minutes. The supernatant thereof wasfurther centrifuged at 20000 g for 20 minutes to obtain a crude synapsefraction. The crude synapse fraction was added with a compound of thepresent invention and incubated at 37° C. for 30 minutes. After adding[3H]choline (1 μM), the mixture was further incubated at 37° C. for 10minutes. Another crude synapse fraction was incubated at 37° C. for 10minutes and used as the control. The reaction was discontinued byfiltering the mixture with suction on a Whatman GF/B filter. Theradioactivity on the filter was measured by a liquid scintillationcounter and the measured value was regarded as the amount of HACU. Theamount of protein was determined in accordance with the method ofBradford (Anal. Biochem., 72, 248(1976)). The results are shown in Table11.

                  TABLE 11                                                        ______________________________________                                        Improvement (% base on control)                                                                  [*P<0.05]                                                                     [**P<0.01]                                                 Example 10.sup.-8 M                                                                            10.sup.-7 M                                                                            10.sup.-6 M                                                                          10.sup.-5 M                                                                          10.sup.-4 M                           ______________________________________                                         1       7        11       8      2       2                                    2       6        10       7      8      11                                    3      -1        13       7     23**     7                                    5       20**     4        18    19     --                                     6       3        10       4     10     --                                     9       0        7        5     13     --                                    10       11       15       26*   44**   --                                    11       11*      10       10*   10      -1                                   12       4        8        17    31*    --                                    15       3        5        7     11      -4                                   16       9        2        9      4     --                                    17       7       -1       -2      3      20                                   19       4        10       14     6      13                                   21       11*      9        11    19*      4                                   22       0        1       -3     10       6                                   25       21*      19       19*   31      22**                                 26       4       -3        9     14       2                                   27       5        18       5     18     -11                                   30       8        17       13    28*    --                                    34       10*      13*     -3     14     --                                    35       11**     17*      20**  21**   -16                                   36       18       15       3     19*    --                                    39       9       -7        13    16       2                                   41       8        8        19*   25**    -4                                   42       1        18       17     9     -13                                   45       0        2        6     14     --                                    52       6        13       11    10       7                                   54       5        18**     15*   14*    --                                    55       20**     25*      26*   36*    -30                                   58       4        5        7     25      15                                   59       5        16*      22*   30*    --                                    61       14       3        21*   25      23                                   63       10        13*     19    31*    --                                    ______________________________________                                    

What is claimed is:
 1. A 4-acylaminopyridine derivative represented bythe following formula (I): ##STR641## wherein R¹ represents a C₂ -C₆alkyl group or a group represented by the following formula (II):##STR642## wherein R² and R³ together with the nitrogen atom to whichboth R² and R³ are attached represent ##STR643## and n represents 0 oran integer from 1 to 3; ##STR644## represents ##STR645## wherein each ofR¹⁰ and R¹¹ independently represents a hydrogen atom or a C₁ -C₄ alkylgroup; and ##STR646## represents ##STR647## and a pharmaceuticallyacceptable acid addition salt thereof.
 2. A 4-acylaminopyridinederivative according to claim 1, wherein R¹ represents a grouprepresented by the following formula (II): ##STR648## wherein R² and R³together with the nitrogen atom to which both R² and R³ are attachedrepresent ##STR649## and n represents 0 or an integer from 1 to 3; and apharmaceutically acceptable acid addition salt thereof.
 3. A4-acylaminopyridine derivative according to claim 1, wherein R¹represents a group represented by the following formula (II): ##STR650##wherein R² and R³ together with the nitrogen atom to which both R² andR³ are attached represent ##STR651## and n represents 1; ##STR652##represents ##STR653## wherein R¹⁰ and R¹¹ independently represent ahydrogen atom or C₁ -C₄ alkyl group, and a pharmaceutically acceptableacid addition salt thereof.
 4. A 4-acylaminopyridine derivativeaccording to claim 1, wherein R¹ represents a group represented by thefollowing formula (II): ##STR654## wherein R² and R³ together with thenitrogen atom to which both R² and R³ are attached represent ##STR655##and n represents 1; ##STR656## represents ##STR657## wherein R¹⁰ and R¹¹represent methyl; and a pharmaceutically acceptable acid addition saltthereof.
 5. A pharmaceutical composition comprising a pharmaceuticallyeffective amount of a 4-acylaminopyridine derivative as defined in claim1 or a pharmaceutically acceptable acid addition salt thereof togetherwith a pharmaceutically acceptable adjuvant.